Endocrinology, Menstrual cycle, Menopause and. Prof Bev Lawton (Anna Fenton) Centre for Women s Health Research Victoria Unversity Wellington

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1 Endocrinology, Menstrual cycle, Menopause and Management Prof Bev Lawton (Anna Fenton) Centre for Women s Health Research Victoria Unversity Wellington

2 Female Menstrual Cycle Relevance to psychiatry? Missing history, missing link? Another arm to therapy? Management? Reducing silo medicine

3 Should Psychiatrists be prescribing oestrogen therapy to their female patients? BJPsych 2013

4 The Obsterician- Gynecologist s role in detecting, Preventing and treating Depression Obstet Gynecol 2017

5 Hormone Roller Coaster

6 Hypothalamic-pituitary ovarian axis Feedback hormones Hypothalamus GnRH Steroids Pituitary Inhibin Gonadotropins: - LH, FSH Ovary

7 Hormone levels over a normal menstrual cycle

8 Estrogens and the CNS

9 Rats/Mice Long term oestradiol changes social behaviour and gene expression in the brains of rats (Garcia 2017) Estradiol treatment in rats provides lasting enhancement of memory and brain oestrogen receptor activity (Pollard 2018) Rhesus monkeys oestrogen increases dendritic numbers in hippocampus and prefrontal cortex (Hara 2015)

10 Humans Estrogen HRT may preserve neurologic function and reduce the risk of dementia if started early in menopause (cohort data) Keeps study(rct) 75 women (mean age 53 years) MRI assessments at Mayo clinic at 18, 36, 48 months during treatment and 3 years after treatment. Cortical volumes declined in both groups but volume of the dorsolateral prefrontal cortex was preserved more in E2 group at 3 years (Kantarci 2018)

11 Estrogen, progesterone and neurotransmitters Estrogen lifts mood, regulates activity and synthesis of serotonin and acetylcholine Interacts with noradrenaline and dopamine Progesterone, alters the GABA system and enhances MAO activity which decreases noradrenaline, dopamine and serotonin Progestogens may lower mood and enhance sedation

12 Mood and the menstrual cycle Individual reactions to hormone cycle changes : PMS/PMDD Post-natal depression Menopause related mood changes, anxiety and psychosis Migraine The change in hormone levels is the problem Recurrent at different stages of reproductive lives.

13 Hormonal Soup

14 History Is the mood disorder cyclical? Before periods Ask about post natal depression Previous episodes of depression LMP? Previously stable Night sweats?

15 Menstrual Mood disorders

16 Sally (45 years of age) PMS symptoms are getting worse- become crippling Gets very angry for the second half of the cycle Negative self talk,memory shot, affecting work,dark places Has 2 young children- not safe for 2 days of the month Period comes- lights get switched back on Feels better when she is pregnant, felt awful on the depo provera

17 Menstrual mood disorders PMS/PMDD increase with age, particularly after 35yrs Hormone swings mid-cycle and pre-period A cascade of changes in neurotransmitters and hormones occurs leading to physical and psychological sx. PMS before 30yrs there is often an underlying hormone disorder, particularly polycystic ovary syndrome

18 Mood swings, PMS symptoms Irritability, depression, anxiety, Bloating, fluid retention, breast tenderness, Sugar cravings, Headaches and poor sleep Tell them they are not going mad and we can alleviate symptoms although it may take time

19 Premenstrual Syndrome 40% of reproductive age women report sx of PMS 3-8% meet the criteria for PMDD. PMDD :50-75% lifetime incidence of psychiatric disorders Mutations in the estrogen receptor have been detected in women with PMDD Sx begin after ovulation and resolve early in the cycle There is always a clear window without sx during the later follicular phase of the cycle The pattern is consistent over 2-3 cycles Huo et al., Biol Psychiatry. 2007;62(8):925-33

20 Hormone levels over a normal menstrual cycle

21 Reducing hormone swings Diet/lifestyle/ exercise Calcium/magnesium Yaz- Anti-androgen,anti-mineralocorticoid Spironolactone Cyproterone- Anti-androgen and anti- Cyproterone- Anti-androgen and antigonadotrophic (FSH,LH) SSRIs Rapid onset of action Medically-induced menopause + estrogen/progestogen (GnRH agonistszoladex)

22 Use of oestrogens Patch in luteal phase HRT (half a Trisequens) Add back progesterone if uterus present Take a good Hx and follow up

23 Polycystic ovary syndrome Genetically determined metabolic disorder 5-10% of women regardless of ethnicity Insulin resistance triggers weight gain and excess androgen production Irregular periods, acne, hirsutism, alopecia and/or weight gain. They may have no sx at all Effects on fertility and CV health

24 Menopause

25 The Menopause What Is IT! Simply means stopping of periods It represents a significant endocrine (hormone) change in a women. Average age is 51.

26 Definitions Menopause The final menstrual period Perimenopause The transition when periods begin to change in length and sx may begin to occur Postmenopausal 12 months after the final menstrual period

27 Definitions Early menopause Last period between 40and 45 yrs Premature menopause Last period before 40yrs May be spontaneous or induced by surgery or cancer treatment

28 Diagnosis of menopause Information is power- women need reassurance this is normal Need to take a good history timing and symptoms 80 % of women have symptoms Blood tests are not helpful

29 The menopausal transition Takes about a decade Early signs menstrual cycle shortens by 2 3 days, detectable at about age ,2 infertility oocyte aging, increased incidence of anovulation 3 basal temperature up in 30 50% of cycles after 40 years age 4,5 1 Lenton 1984; 2 Klein 1996; 3 Treloar 1970; 4 Dòring 1963; 5 Vollmann 1977; 6 Baker 1963; 7 Richardson 1987

30 Determinants of the age of menopause oophorectomy, e.g. for endometriosis, cancer chemotherapy, e.g. cyclophosphamide ovarian irradiation hysterectomy (up to 4 years earlier) familial and genetic factors (e.g. ER-α polymorphism, twinning) cigarette smoking by about 2 years

31 Symptoms Symptoms clearly related to estrogen deficiency Vasomotor symptoms Vaginal or genital dryness Recurrent UTIs Joint pain or stiffness Generalized aches and pains Sexual dysfunction Mood disturbance palpitations Barnabei et al., 2005 Obstet Gynecol, Welton et al., 2008 BMJ KEEPS Study, NAMS 2012

32 Menopause Symptoms Who gets symptoms? 5-10 yrs before periods stop and reflect the swings in hormone levels 20% of women will have long-term sx Different ethnic groups may have different experiences of menopause May be last straw- Grief reactions, co-morbidities (including mental health), other life stresses A surgical or chemo-induced menopause have worse symptoms for longer.

33 These symptoms can be debilitating Unable to function Sleep or flushes? Impacts on partners and children Unable to have intercourse due to vaginal dryness/atrophy

34 Menopause and mood Perimenopausal depression is common Risk of new onset depression increases two fold Previous depression strongest predictor of depression during midlife years The role of estrogen deficiency vs sleep deprivation in altering mood and cognitive function is debated Anxiety and sleep. Sciller et al Comprehensive physiology 2016 Worsley et al., Maturitas (2):111-7 Gibbs et al., Women Health Issues (5):301

35 Peri-menopausal Depression Take a good history You may be the only ones seeing these women regularly Be aware of increased risks of mood disturbance Check other causes

36 Treating depression with estrogen? 57 women with depression.(cesd 27-29) RCT oestradiol vs placebo mean age 60. No difference in depression scores after 8 weeks (Morrison 2004)- 50 women RCT oestradiol vs placebo mean age 50. Remission of depression occured in 17 (68%) of women on oestradiol compared to 5 (20%) on placebo (Soares 2001) Women with past PMD treated with HRT showed increased depression when HRT with drwan (RCT) (Schmidt 2015JamaPsych)

37 Prevention Does 12 months transdermal oestradiol and progesterone prevent development of depression compared to placebo? (RCT) 172 peri-menopausal and post menopausal women 32.3% of women using placebo developed clinically significant depressive symptoms compared to 17.3 % of women on oestrogen Is it a preventative treatment? Gordon FEB 2018JAMA Psychiatry

38 Oestrogen and Psychiatric disorders Menopause associated with a worsening of Bipolar illness (Marsh 2012) Comorbidity between PMDD and BD is associated with worse clinical outcomes and increased illness burden.(slyphenko 2017) Oestrogen (adjunct) versus placebo for women with schizophrenia:cochrane protocol June 2016

39 Management of menopause

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41 Menopausal Hormone Therapy Estrogen alone (oral or transdermal) Estrogen + progestogen (oral or IUS) Benefits: Reduces sx Reduces fracture risk Reduces all cause mortality Estrogen alone reduces breast cancer risk?reduces risk of colon cancer,risk of CAD Risks: Age related CVA/VTE, stroke, gallbladder Progestogen related breast cancer

42 Menopause transition Flushes Night sweats Joint and muscle aches Sleep disturbance Mood and cognitive change Vaginal dryness Sexual dysfunction Genito-urinary problems Osteoporosis Increased CAD risk

43 Menopausal Hormone Therapy The most effective treatment for symptom control days There is no consistent formula that works for every woman. Adjustment of doses is critical Mood improves in 68-80% of women

44 Surgical Menopause Women with a surgical menopause may require higher doses of estrogen to settle sx The risks of menopause before age 45yrs are substantial. Hormone therapy should be used unless there are contraindications. HRT should be continued until the normal age of menopause

45 Alternatives to HRT Exercise CAMS: Remifemin, St John s wort, acupuncture, hypnosis, CBT, mindfulness SSRI: escitalopram, paroxetine*, venlafaxine Gabapentin Cetirizine Clonidine Stellate ganglion blockade

46 Hypnosis Elkins et al., Menopause 2013

47 Stellate ganglion blockade

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49 Your practice Be aware and proactive Take a good history? Prescribe 7-21 days the magic oestrogen window Buddy up with someone who has an interest USE Australasian Menopause Society Info

50 BEST PICK Hysterectomy Estradot 50 (25, 50,75,100 micrograms estradiol per day) 3 to 4 week trial Monitor night sweats, sleep, mood, vaginal dryness Make a list of active problems you think may be related to hormones

51 Patient Informed consent risks and benefits She will tell you whats changed I don t feel myself Rage Ask about QoL Talk about hormones and mood and see if she wants to try hormones for a month. They will either work or not Check your list when she returns

52 Risks and benefits Informed consent Australasian Menopause Society pamphlets Clotting Breast cancer (? Increased) All about seeing if this change in mood/ psych state is being affetced by the co-morbidity of menopause

53 Best PicK: No hysterectomy Estradot Utrogeston 100mg ( micronised progesterone) Explain risks, benefits and side effects Bleeding ( 17%) will bleed in the first year

54 Why prescribe Will find out if the cause of the mood upset is hormonal If it works ( like a light going on - a switch! Back to normal!) Familiarise yourself with the local doctors that Have expertise in this area.(ams site

55 Take home messages Hormones have significant effects on neurotransmitters and mood Individual women have increased vulnerability to normal hormone changes A rocky menopause superimposed over an existing psychiatric illness may increase morbidity

56 Practical Approach Think hormonal soup Accross the life cycle Identify those women at risk Be pragmatic Trial appropriate treatment- 28days!

57 Final Thoughts 1. Trial of HRT if you feel depression or relapse is related to menopause. 2. Think about reproductive mood disturbance in the life course-post partum, premenstrual and post menopausal 3. Be proactive- have a plan for all women as they age 4. Treatment and prevention?

58 Quality of Life

59 Kia Ora Centre for Women s Health Research Research making a difference to women